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Human Molecular Genetics Pages 1289-1293

SCA6 is caused by moderate CAG expansion in the [alpha]1A-voltage-dependent calcium channel gene
Introduction
Results
   The range of normal (CAG)n repeat length in the SCA6 gene in octogenerians
   Frequency of the SCA6 (CAG)n expansion in sporadic ataxia patients and in autosomal dominant SCA
   Transmission stability of the normal and expanded SCA6 (CAG)n repeat
   Correlation of the (CAG)n repeat size with age at onset
Discussion
Materials And Methods
   DNA analysis
Acknowledgements
References
Table

SCA6 is caused by moderate CAG expansion in the [alpha]1A-voltage-dependent calcium channel gene

SCA6 is caused by moderate CAG expansion in the [alpha] 1A -voltage-dependent calcium channel gene Olaf Riess1,*, Ludger Schöls2, Heike Böttger3, Dagmar Nolte4, Ana Maria Menezes Vieira-Saecker1, Carmen Schimming5, Friedmar Kreuz6, Milan Macek Jr7, Alice Krebsová7, Milan Macek Sen.7, Thomas Klockgether8, Christine Zühlke3 and Franco A. Laccone5

1Molecular Human Genetics, Ruhr-University, D-44780 Bochum, Germany, 2Department of Neurology, St. Josef Hospital, Bochum, Germany, 3Institute for Human Genetics, University Lübeck, Lübeck, Germany, 4Institute for Human Genetics, University Giessen, Giessen, Germany, 5Institute for Human Genetics, University Göttingen, Göttingen, Germany, 6Institute of Clinical Genetics, University Hospital, Technical University, Dresden, Germany, 7Department of Medical Genetics II, University Hospital Praha, Praha, Czech Republic and 8Department of Neurology, University of Tübingen, Tübingen, Germany

Received April 2, 1997; Revised and Accepted May 27, 1997

Recently, moderate (CAG)>20 repeat expansions in the [alpha]1A-voltage-dependent calcium channel gene (CACNL1A4) have been identified in a previously unmapped type of SCA which has been named SCA6. We investigated the (CAG)n repeat length of the CACNL1A4 gene in 733 patients with sporadic ataxia and in 46 German families with dominantly inherited SCA which do not harbor the SCA1, SCA2, or MJD1/SCA3 mutation, respectively. The SCA6 (CAG)n expansion was identified in 32 patients most frequently with late manifestation of the disease. The (CAG)n stretch of the affected allele varied between 22 and 28 trinucleotide units and is therefore the shortest trinucleotide repeat expansion causing spinocerebellar ataxia. The (CAG)n repeat length is inversely correlated with the age at onset. In 11 parental transmissions of the expanded allele no repeat instability has been observed. Repeat instability was also not found for the normal allele investigating 431 meioses in the CEPH families. Analyzing 248 apparently healthy octogenerians revealed one allele of 18 repeats which is the longest normal CAG repeat in the CACNL1A4 gene reported. The SCA6 mutation causes the disease in ~10% of autosomal dominant SCA in Germany. Most importantly, the trinucleotide expansion was observed in four ataxia patients without obvious family history of the disease which necessitates a search for the SCA6 (CAG)n expansion even in sporadic patients.

INTRODUCTION

The autosomal dominantly inherited spinocerebellar ataxias (SCA) are a group of clinically and genetically heterogeneous disorders with a prevalence of ~1 in 100 000 (1 ). Clinically, the patients suffer from variable combinations of ataxia of gait, stance and limbs, dysarthria, ocular motor disorders, pyramidal and extrapyramidal signs, incontinence, peripheral neuropathy and dementia (2 ). The age at onset can vary considerably within and among families ranging from 5 to 65 years. The duration of the disease is ~20 years. Mainly based on genetic linkage data SCA has been divided into subgroups and named with increasing numbers. At least seven gene loci are responsible for SCA. For SCA1, -2 and -3 the genes have been mapped to human chromosomes 6 (3 ,4 ), 12 (5 ,6 ) and 14 (7 ,8 ), respectively, and the disease causing mutations have been identified as expanded and unstable (CAG)n trinucleotide repeats (9 -13 ). The function of these genes is still unknown. In a Utah kindred the disease phenotype (SCA4) cosegregates with markers on chromosome 16q (14 ) and in SCA5 the gene has been linked to chromosome 11 in the descendants of the grandparents of Abraham Lincoln (15 ). Furthermore, a sixth locus (SCA7) characterized by spinocerebellar ataxia with retinal degeneration has been mapped to human chromosome 3 (16 ). For SCA4, -5 and -7, respectively, the disease causing mutations have still to be identified.

The search for expanded CAG repeats in SCA families has finally led to the identification of the SCA6 gene (17 ). The SCA6 gene encodes an [alpha]1A-voltage-dependent calcium channel gene (CACNL1A4) which is known to be important for normal Purkinje cell function and survival (17 ). This gene has previously been mapped to human chromosome 19p13 (18 ). Here we provide data on the frequency of the SCA6 mutation in German families with autosomal dominant spinocerebellar ataxia. Furthermore, we investigated whether this mutation is also found in other sporadic types of cerebellar ataxias. We analyzed the stability of the normal CAG repeat during parental transmission in the CEPH pedigrees and of the expanded allele in eight parent/child pairs carrying the SCA6 mutation.

RESULTS

The range of normal (CAG)n repeat length in the SCA6 gene in octogenerians

In order to define the range of the (CAG)n repeat length in the SCA6 gene in normal chromosomes we investigated 248 apparently healthy Caucasians older than 80 years (496 chromosomes). These octogenerians did not present any neurological or psychiatric symptoms at the time of blood sampling. There was no family history of neurological disorders in any of these persons. The most frequent alleles consist of 11 (31.25%), 12 (21.37%) and 13 (35.08%) CAG repeats (Fig. 1 ). The smallest allele found consists of just four repeat units. Most interestingly, we found one person harboring 18 CAG repeat blocks in the SCA6 gene. This is the largest normal allele in the SCA6 gene reported. The overall heterozygosity rate in this sample was calculated as 0.77. Analysis of the (CAG)n repeat size in 149 unaffected relatives of SCA patients revealed no difference in the allele frequency compared to the group of octogenerians (data not shown). In the former group the largest (CAG)n repeat size was 14.


Figure 1. Distribution of (CAG)n repeat sizes in the SCA2 gene in 733 patients with sporadic ataxia and in 32 patients harboring the SCA6 mutation.

Frequency of the SCA6 (CAG)n expansion in sporadic ataxia patients and in autosomal dominant SCA

We analyzed 733 patients with idiopathic sporadic progressive ataxia and an age at onset ranging from 3 to 80 years for the CAG repeat expansion in the SCA6 gene. Disease manifestation in these patients was regarded as sporadic since no other family member in at least two preceding generations had presented with cerebellar symptoms (gait disturbances, dysarthria, dysphagia, motor skills). Patients with ataxia caused by ethanol abuse or other intoxications, paraneoplasia, malformation, vascular defects, inflammation or autoimmune diseases were excluded. As already mentioned, CAG repeat expansions in the SCA1, SCA2, and SCA3 loci, respectively, were not found in these patients. Furthermore, a (GAA)n repeat expansion in the novel X25 gene causing Friedreich's ataxia (19 ) was excluded for these sporadic patients.

Seventy-six percent of the sporadic patients were heterozygous for the (CAG)n repeat, corresponding to the heterozygosity rate in the control individuals. The distribution of the normal alleles did not differ significantly from the frequency in the normal population (data not shown). Mutation analyses revealed a (CAG)>21 repeat expansion in the SCA6 gene in foursporadic patients. These patients carried small CAG expansions of 22 and 23 units and developed first symptoms at 47, 53, 54 and 60 years, respectively. Retrospective revision of the family history in these patients revealed that the fathers of two patients were killed during world war II and the mother of one patient died at age 59 from heart failure. However, these parents did not present with movement abnormalities nor were cerebellar symptoms detected in the relatives of the patients. The mother of one patient who presented with first symptoms at age 53 developed faint gait difficulties beyond the age of 88. In this case DNA was not available for mutation analysis. However, in all four kindreds of this family no further individual was affected.

Patients from 46 families with autosomal dominant inheritance of the disease were analyzed. CAG repeat expansions in the SCA1, SCA2 and MJD/SCA3 genes had been excluded in the families. In our sample, the expanded alleles of the SCA6 gene carried from 22 to 28 repeat units (Fig. 1 ). Previously, an expanded allele of 21 repeats has been described in a single SCA6 patient (17 ). Thus, the difference between the largest normal allele of 18 repeats and the smallest expanded allele amounts to just three CAG units. In total, 28 patients from 19 families were identified harboring the expanded (CAG)n repeat within the SCA6 gene (Table 1 ). Thus, SCA6 is less frequent than SCA1, SCA2, or SCA3, respectively. However, we found striking regional differences in the frequency of the SCA types. For instance, the prevalence of SCA6 appears to be slightly higher than SCA1 or SCA2 in the Western part of Germany (Table 1 ). The genetic cause for 27 SCA families with autosomal dominant inheritance (14%) remains to be identified.

Table 1 . Frequency of different types of autosomal dominant SCA in German families
Center SCA1 SCA2 SCA3 SCA6 Unknown Total
Bochum 6 7 30 12 14 69
Göttingen 32 12 24 5 5 78
Lübeck 11 4 12 2 8 37
Total number 49 23 66 19 27 184
Percent 27 13 36 10 14 100

Transmission stability of the normal and expanded SCA6 (CAG)n repeat

We investigated the size of the SCA6 (CAG)n repeat during transmission analyzing the CEPH pedigrees and additional large families of German ancestry. In total 431 meioses were counted. No change in size of the transmitted (CAG)n blocks was observed indicating that the repeat is stably transmitted on normal alleles (data not shown).

In our SCA6 families we studied 11 events of parent to child transmission. Most strikingly and in contrast to other spinocerebellar ataxias, all transmissions (seven maternal, four paternal) of the expanded alleles were characterized by stable repeat sizes independent of the sex of the transmitting parent and of the length of the expanded allele (22, 23, 26 and 27 CAG repeat units, respectively). However, age at onset of the patients differed by up to 21 years from parental onset (age at onset in the father 71 years, in the son 50 years). Two offsprings developed first symptoms later than the affected parents (7 and 13 years, respectively).

Correlation of the (CAG)n repeat size with age at onset

Further, we analyzed whether the repeat size might influence the age at onset in patients with the SCA6 mutation. Age at onset was retrospectively determined from 32 patients. As in the other (CAG)n trinucleotide repeat disorders, the age at onset of the disease is inversely correlated with the expanded (CAG)n repeat length (r = -0.782, P = 0.0000; Fig. 2 ). However, the age at onset between patients with one specific repeat size differs clearly. For instance, patients carrying 22 CAG repeats developed first symptoms between the ages of 42 and 71. Mean age at onset of all SCA6 patients was 51.35 +- 10.9 years. All patients carrying expanded alleles of 26-28 CAG repeats manifested between the ages of 30 and 40. Older patients presenting first symptoms beyond age 50 harbored 22 or 23 repeat blocks, respectively. Seven patients (22%) developed the disease at age 60 or later indicating that the SCA6 mutation counts for late onset forms of SCA.


Figure 2. Correlation between the expanded (CAG)n repeat length in the SCA6 gene and the age at onset in 32 SCA6 patients. The correlation coefficient was calculated for a linear regression using the computer package Excel (r = -0.782, P = 0.000).

DISCUSSION

SCA6 belongs to a group of late manifesting neurodegenerative disorders including SCA1, SCA2, SCA3/MJD, Huntington disease (HD), spinobulbar muscular atrophy (SBMA) and dentatorubral pallidoluysian atrophy (DRPLA) (9 -13 ,20 -23 ) which are caused by the expansion of unstable (CAG)n repeats. In contrast to these diseases, small (CAG)>20 expansions are causative for the neuronal cell death in SCA6. The (CAG)n block in the SCA6 gene is also translated into a polyglutamine stretch. Point mutations in the CACNL1A4 gene have been identified in patients with episodic ataxia type 2 (EA) and familial hemiplegic migraine (FHM), respectively (24 ). These disorders and SCA6 should therefore be considered as allelic.

An inverse correlation has been demonstrated between the number of (CAG)n repeats and the age at onset in trinucleotide diseases (9 -13 ,20 -23 ,25 ,26 ). We also observed an inverse correlation between (CAG)n repeat size and the age at onset in our SCA6 patients (r = -0.782, P = 0.000) despite the small size of the expanded allele. These small expansions are the smallest known to be causative for neurodegeneration thus far and are in the range of normal alleles in all other trinucleotide disease genes. One might argue that in the SCA6 gene the flanking translated sequence is less protective against the `gain of function' mutation. This hypothesis finds some support in the recent observation that transgenic animals carrying an expanded (CAG)n repeat in the Ataxin-3 gene will preferably develop symptoms with shortened cDNA constructs but not with the full length clone (27 ). It is interesting to recognize that an expanded allele of the SCA6 gene shows low variability (59% of expanded alleles consist of 22 CAG blocks and 22% of 23 units) and no transmission instability has been observed in the limited number of meioses studied. This is in striking contrast to all other trinucleotide repeat diseases where ~70% of the expanded alleles are unstably transmitted (28 ). It is most likely that this transmission stability of the expanded SCA6 (CAG)n block is due to the small repeat size. Despite the fact that instability of the expanded alleles in parental transmission has not been observed the age at onset varied significantly between the parents and their offsprings. Also, unrelated patients with the same repeat length show great variation in onset age. This suggests that other genetic factors as has been discussed for MJD (29 ) or epigenetic influences might modify age at onset in SCA6.

The cloning of four genes responsible for SCA allows definitive and simple diagnosis in almost 85% of autosomal dominant ataxia families in Germany. Based on this study, ~10% of all German families with dominant ataxias harbor the SCA6 mutation. However, large geographic differences exist in the prevalence of the four SCA types for which the causative trinucleotide mutations have been defined (Table 1 ). SCA1 appears to be more common in the north and the central part of Germany, whereas SCA3 is the most common type in the west (Northrhine Westfalia; 25 ), followed by SCA6. SCA2 appears to be more common in Bavaria and in families of Austrian ancestry. About 15% of the families with autosomal dominant SCA do not harbor any of the four mutations. It will be interesting to reveal whether these families are linked to the SCA4 or SCA5 loci (14 ,15 ) and if they are caused by a (CAG)n expansion. The isolation of CAG repeat containing genes from cDNA libraries (30 -32 ) will most likely accelerate further identifications of trinucleotide diseases.

MATERIALS AND METHODS

DNA analysis

Genomic DNA of patients with cerebellar ataxias and unaffected individuals was extracted from peripheral white blood cells (33 ). Genomic DNA (100 ng) was amplified by radioactive PCR using the primer pair S5F1/S5R1 (17 ) in a total volume of 10 [mu]l. Amplification was carried out for 35 cycles with denaturation at 95oC for 1 min, annealing at 60oC for 1 min, and extension at 72oC for 1 min, in a Robocycler (Stratagene). DMSO was added to a final concentration of 10% to avoid unspecific amplification products. PCR product sizes were determined by comparison to an M13 sequencing ladder. Alternatively, primers were labeled with fluorescence dye and the size of the PCR product was estimated on an automatic analyzer ABI 373.

ACKNOWLEDGEMENTS

This study would not have been possible without the help of the SCA families which is gratefully acknowledged. CEPH kindly provided DNA samples to analyze repeat stability. We thank Professors Epplen, Engel, Schwinger, Müller and Przuntek for their support. O.R. thanks M.Gossen for critical reading of the manuscript and B.Weber for DNA samples. F.A.L. thanks Susanne Herlt for technical assistance. This work is supported by the Deutsche Forschungsgemeinschaft (O.R.). M.M.Sr. and M.M.Jr. are supported by IGA MZ CR (#2899-5, 3526-3, 4124-3, 2861-5) and by GA CR (#1148-6 and 305/95/1606).

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*To whom correspondence should be addressed. Tel: +49 234 700 3831; Fax: +49 234 709 4196; Email: olaf.riess@rz.ruhr-uni-bochum.de

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